14-60457098-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_174978.3(C14orf39):c.1180-3C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C14orf39 NM_174978.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.77

Genes affected

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 14-60457098-G-C is Pathogenic according to our data. Variant chr14-60457098-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 992824.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-60457098-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C14orf39	NM_174978.3	c.1180-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000321731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C14orf39	ENST00000321731.8	c.1180-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_174978.3	P1
C14orf39	ENST00000557138.5	c.*494-3C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 52 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 23, 2021

- -

Non-obstructive azoospermia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular and Cell Genetics Laboratory, University of Science and Technology of China

Jan 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	16
Dann	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1891315296; hg19: chr14-60923816;